Category Archives: The Literature

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We chemists love our jargon. Oftentimes for good reason; it would be cumbersome to describe a material as “having a tendency to absorb moisture from the air” over and over again. Instead, the word hygroscopic gets the point across succinctly. Examples of this sort of jargon abound, with the IUPAC Gold Book defining some 6400 unique terms.

The type of language that’s used in the chemical literature actually gives us a window into the work being done over time. A while back Stu compiled 115 years of JACS article titles into word clouds binned by decade. The result? A visual representation of a century of chemical research. While you see words like “synthesis,” “stereochemistry,” and “nano” reflecting changes in research interests over the years, you also see steady usage of words like “new,” “efficient,” “direct,” and “novel.”

This brings up a second set of chemistry jargon terms which generally do not describe specific and well-defined concepts. Instead of jargon, one might just call these terms adjectives common in the chemical literature. We like to poke fun at the use of words like novel, concise, and robust. Who gets to decide if a preparation is concise, or if a given synthesis is more or less robust than those that preceded it? After all, there’s more than one way to talk about synthetic efficiency.

Bringing me to my topic du jour, just today I came across the umpteenth paper ascribing the mechanism of a particular reaction to the “steric and electronic properties” of the starting materials.

16,000+ results, see I’m not crazy

What other kinds of properties can reactants have? Aren’t all properties just emergent from either sterics or electronics? The chemical-reductionists among us would argue that all properties are emergent from quantum mechanics anyway:

@mantalek Especially since steric is just one type of electronic effect

It’s not factually incorrect to say that a reaction behaves the way it does because of sterics and electronics, but that description could apply to literally every reaction. Find me a reaction mechanism that isn’t governed by S&E, and we’ll talk. This kind of language treads dangerously close to the territory of the not even wrong.

The S&E argument, like many other broad but factually true statements from the literature, is in all likelihood just a euphemism for “it is what it is.” Maybe it’s time to assemble a list of useless phrases for a literature bingo game…

Today I’m back in the swing of planning out more traditional multi-step organic syntheses, which is something I have’t done in a while. Of course a major part of that is combing through the literature — and dealing with all the idiosyncrasies that entails. Right off the bat, I noticed that Reaxys doesn’t play terribly well with Google’s Chrome browser, something I’d never encountered before being a member of the SciFinder tribe.

One of the other considerations of perusing the synthesis literature is deciphering the myriad of acronyms used by authors. It’s rather inconvenient to type tert-Butyl(chloro)diphenylsilane over and over again, so we’ve usually use “TBDPSCl” for short. This, and many other short hands are universally known in the field. And there are whole lists of common ones. But every once in a while you come across one you’ve never seen before.

Enter “APTS.” From a paper on synthetic a-galactosylceramides, we see APTS used in combination with benzaldehyde dimethyl acetal to selectively protect the 4 and 6 positions in galactose. My early morning, caffeine-deprived brain failed to notice the Abbreviations section at the end of the paper and began scouring the internet for traces of APTS used in the chemical literature. Undeterred, but finding only apartment listings, I noticed the author affiliations — all authors are from non-US institutions, and one in particular from Institut Parisien de Chemie Moleculaire in Paris, France.

Knowing APTS must be some sort of acid catalyst, and having a very broken understanding of the French language, two and two were put together and APTS became acide paratoluènesulfonique, or para-toluenesulfonic acid.

The Wikipedia page for para-toluenesulfonic acid does list “PTSA” as an acronym, but I think I’ve only seen it written “TsOH” or “pTsOH.”

A couple weeks ago, I talked about a patent published by the Klapötke group in which a series of bis(aminotriazole) salts were prepared and characterized. It’s pretty neat stuff, and the molecules showed pretty solid energetic performance across the board.

Well, as luck would have it, another publication from the same group came out last week. This piece is a followup on some chemistry from back in 2015 [1], wherein they prepared some triazole tetrazoles bearing nitro, azido, and amino ring substituents (compounds 5–8). You know, for the severely carbon-averse out there. A quick snapshot of this chemistry is reproduced below. Compound 5 is afforded in ~64% overall yield in 5 steps. The process chemists out there will appreciate this detail: all compounds are prepared by chromatography-free means.

Get your azoles, now with 33% more nitrogen! — Reproduced from [1]

As one might expect, the sensitivities of the four parent compounds to external stimuli (impact, friction, ESD) ranged from “quite” to “extremely.”

The scope of the recent offering is to use these materials as energetic anions with various metallic and non-metallic cations [2]. Since the tetrazole proton is basically holding on for dear life — as evidenced by a 1H chemical shift of 16.19 ppm — preparing these salts was a matter of treating the parent compounds with a basic solution of the desired cation. The goal here being use metal cations (a–c) to produce sensitive primary explosives, and nitrogen-rich cations (d–h) to produce less sensitive secondary explosives.

Silver’s an interesting choice; I’m generally content to not find myself in the same room as large quantities of any compound with both “azido” and “silver” in its name, but nonetheless, compound 6c exists, albeit only briefly. The compound has impact and friction sensitivities below the minimum test threshold using the BAM method. To quote the text:

The yield [of 6c] was not determined owing to the extremely high friction sensitivity of this compound.

The cesium analog, 6b, fares slightly better. It holds together long enough to get some spectroscopy data, and the impact, friction, and ESD sensitivities of this compound were high, but measurable. The text notes the ESD value is slightly less sensitive than lead azide, which is commonly employed in blasting caps. But high sensitivity alone does not necessarily make for a good primary explosive — the material must be capable of initiating detonation in a secondary explosive. To that end, a mass of RDX was loaded into a copper tube sealed at one end, and 50 mg of compound 6b was layered on top. Firing with an electrical detonator resulted in the image below:

So it does in fact kick off secondary explosives quite nicely — fragments of metal casings are often a welcome sign in energetic research. It is also noted that compounds 6a–c all undergo a deflagration to detonation transition (DDT), although it’s not clear how this was determined. Small samples of explosives generally do not detonate unless they are confined or there is a critical diameter present. But I digress.

Now onward to the so-called “nitrogen rich” salts. A total of 14 nitrogenous salts were prepared, however four were only isolable as the corresponding dihydrates: 5d, and 8-2e–g (compound 8 formed the corresponding dianion). The remaining ten demonstrated a very high degree of insensitivity. With the exception of 7e, all were less sensitive than RDX in BAM impact and friction, and ESD tests. Additionally, all were within a 10% margin of RDX in both detonation velocity and detonation pressure according to EXPLO5 calculations. Likewise, almost all burned cooler than RDX.

One major advantage of using nitrogen-based HEDMs is that they are non-oxidative. That is, no oxidizing salts (say, perchlorate, nitrate), and minimal organic nitro-groups, so metal components of gun barrels won’t break down as quickly. Since deflagrations/detonations are far from ideal from a stoichiometry standpoint, you can end up with significant amounts of NO and NO2 (and even HCl if your propellant is ammonium perchlorate). Those gases get pretty warm in armament combustion chambers and can seriously damage barrel bores, which can lead to critical failure. But with nitrogen heterocylces, you reduce the formation of nitrogen oxides and instead form mostly N2, and eliminate chlorine entirely.

So to that end, the authors reformulated two propellants, HN-1 and HN-2 (HN = “High nitrogen”), which are used in very large bore guns. The compositions are mostly RDX, with some TAGzT, a relatively sensitive triaminoguanidinium salt of 5,5′-azotetrazole. Substituting compound 5h, for TAGzT resulted in about a 10% boost in the specific energy of the formulation, with a modest increase in combustion temperature.

This is a perfect example of one of the fundamental challenges of energetics research, which I mentioned in passing in my previous post: you can’t have it all. You can always cram more energy density into a molecule — just stick more nitro groups on it, or replace a triazole with a tetrazole. But increasing the energy density comes at a price, almost without exception: your molecule burns hotter, or is more sensitive, or both. And the authors acknowledge this, stating that while the combustion temperature increases, it is still well below the critical temperature for gun propellants.

The Klapötke group at LMU is marching relentlessly onward with their quest to find new and interesting ways to stick as many nitrogen atoms onto one molecule in as close proximity as (barely) possible for long enough to get NMR data.

You may remember the Klapötke group from Derek’s post over at ItP in the “Azidoazide Azide” issue of Things I Won’t Work With. This is the group that would look at pentazole and think “Gee, I wonder if we could replace that proton with an azide…” I’ve always thought this kind of work was pretty cool; most of these crazy nitrogen heterocycles are practically useless but they serve the important purpose of giving us a better understanding of the nature of chemical bonds at the margin of what is possible.

Klapötke et al is back with a published patent application that showed up on my scanner. This time, they’ve taken a step back from the realm of the ridiculous and have prepared a reasonable looking energetic active ingredient: 3,3′-dinitro-5,5′-bis-triazole-1,1′-diol (and a couple bis salts thereof).

And that structure looks not at all unreasonable. Sure, electron deficient triazoles aren’t the most stable, but that hydroxyl contributes some electron density back to the ring system. Oxygen balance looks good. Slightly under-oxidized, actually, which as a rule gives you a bit of stability back.

But enough with speculation, let’s take a look at the thermal and sensitivity data provided in the text. In energetics, RDX is commonly used as a benchmark: it has good (not great) explosive performance, and it reasonably insensitive to impact, friction, and electrostatic discharge. Interestingly, the application does not present characterization data on the parent diol, but instead offers three salts: dihydroxylammonium (MAD-X1), diguanidinium (MAD-X2), and di-triaminoguanidinium (MAD-X3).

And the lead compound, MAD-X1, outperforms RDX across the board: better sensitivity in all three metrics, high detonation velocity (9.3 km/s to RDX’s 8.7), greater crystal density, higher thermal decomposition onset, larger heat of formation, and lower detonation temperature. As anyone who works in the field knows, it’s really hard to have it all; you can always increase you explosive performance… at the expense of sensitivity. And vice versa. But, as far as performance metrics go, MAD-X1 seems to pretty handily have a leg up on the competition.

Even the synthesis is pretty straightforward and uses decidedly non-exotic reagents. First, oxalic acid is condensed with aminoguanidinium bicarbonate in concentrated HCl, then worked up under basic conditions, affording 3,3′-diamino-5,5′-bis-(1H-1,2,4-triazole) (“DABT”). DABT is then oxidized to the bis-nitro derivative as the corresponding dihydrate, which is fantastic from a energetics processing standpoint. Treatment with potassium peroxymonosulfate affords the anhydrous diol, which reacts subsequently with an ethanolic solution of hydroxylamine, which yields MAD-X1 in 44% overall yield over four steps.

While not as concise as the two-step Bachmann process, which yields RDX from hexamethylenetetramine in 57% overall yield on an industrial scale, Klapötke’s preparation of MAD-X1 appears scalable. Namely, it dispenses with the wildly exothermic nitrolysis process used to make nitramines — if you’ve ever had the pleasure of performing such a reaction you’ll know it’s incredibly easy to end up with a runaway reaction and a resultant yield rapidly approaching zero. Do that on a large scale, and you’ll have a pilot plant rapidly approaching low earth orbit.

Overall, I’m pretty impressed with this compound’s prep and apparent utility. My main criticism is: how’s that alkoxide salt going to hold up in an environment where metals are present? Namely, in a casing or shell. If the the use of picric acid has taught us anything, it’s that acidic energetics tend to not play well with metals. I’d love to see some followup formulation work addressing this issue.

Last night, I was killing some time while waiting for a particularly stubborn 13C-NMR experiment to run by browsing through my company’s library. I came across something particularly interesting there; everyone knows Fieser and Fieser’s classic Reagents for Organic Synthesis, but did you know before that series was published, the duo authored a first-year organic chemistry text book? That’s right, I found an original 1950 edition of Louis and Mary Fieser’s Textbook of Organic Chemistry.

It’s got some really beautiful illustrations, and some discussions you’d probably not find in a more modern o-chem book. I thought the readership here might appreciate some of the artwork:

The cover, complete with debossed gold lettering

We open with electron shells:

Argon was represented by “A” until 1957

Soon, we are met with a discussion about the structure of benzene. Correctly ascertained in 1865, the Fiesers present a short history of alternative benzene structures:

Structural elucidation was a laborious task in the early-to-mid 1900’s. FT-IR was only just discovered in the late 1940’s, and it wasn’t until the 1960’s that is was widely available as a characterization tool. Without mass spectrometry and NMR, chemists had to rely largely on elemental analysis:

A CH combustion analysis apparatus

The principals of stereochemistry were known, and optical rotation could be determined using a polarimeter. Chemists were still a ways off from the digital polarimeters used today:

The text describes a method for hydrogenation of olefins at atmospheric pressure in elegant style:

And distillation:

Next up, my favorite part: a short section on explosive chemistry. Although those picrates land squarely in the category of things I won’t work with:

And did you know that the first chemotherapeutic agent was an organoarsenic compound? The text describes the synthesis of arsphenamine, a treatment for syphilis in the early 1900’s, until it was supplanted by the much safer and more efficacious penicillin.

And check out these subsequent illustrations of steroids and the heme group from hemoglobin:

There’s a Q&A piece in Current Biology (a Cell journal) on Professor Jingmai O’Connor circulating at the moment. Most of it it pretty standard stuff: Why are you a biologist? What’s it like being an American scientist in China? What was your favorite conference?

But for a “young scientist,” two of O’Connor’s answers sure seem old school. One question asked of the professor was “Do you think there is an increased need for scientists to market themselves and their science as a brand?” Her answer (emphasis mine):

I think the idea that scientists need to operate more like a business is becoming a major problem in science recently. There is science and there is business — they are different and should be fundamentally driven by different goals: one, the pure and unadulterated desire for greater knowledge and the other, monetary gain. Branding science puts focus on making your research appealing, which is extremely limiting, and — dare I say? — corrupts the scientific process. There is a lot of fundamental research that needs to be conducted that is not ‘sexy’. Such ‘science branding’ has not yet affected the Chinese Academy of Sciences and for that I’m grateful.

Ignoring how pretentious this comes off as, the idea that making your science “appealing” somehow corrupts it is exactly wrong. Science should be appealing. If your science isn’t appealing, maybe you’re not doing good science. And second, the idea that business and science are mutually exclusive enterprises is laughable. I can point to dozens of fundamental scientific discoveries made by the private sector. It turns out that money is actually a pretty good motivation for coming up with cool new scientific ideas. Conversly, let’s not pretend that all science is driven by “the pure and unadulterated desire for greater knowledge.” This implies that only academic science is true science. But even academic science has a driving force that is decidedly non-scientific.

It gets better (worse?) from here. “What’s your view on social media and science? For example, the role of science blogs in critiquing published papers?”

Those who can, publish. Those who can’t, blog. I understand that blogs can be useful in affording the general public insights into current science, but it often seems those who criticize or spend large amounts of time blogging are also those who don’t generate much publications themselves. If there were any valid criticisms to be made, the correct venue for these comments would be in a similar, peer-reviewed and citable published form. The internet is unchecked and the public often forgets that. They forget or are unaware that a published paper passed rigorous review by experts, which carries more validity than the opinion of some disgruntled scientist or amateur on the internet. Thus, I find that criticism in social media is damaging to science, as it is to most aspects of our culture.

Damn kids, get off my lawn!

That’s a real doozy. The last part reads like that guy who is proud of not having a Facebook account like it’s some sort of accomplishment. But all snark aside, I strongly disagree fundamentally with what O’Connor has to say about blogging and social media with respect to science. I can point to example after example of successful, productive scientists with active social media presences. Again, the two are not by any means mutually exclusive.

But perhaps my biggest problem with this response is how brazenly the author dismisses public criticism and post-peer review in favor of the almighty peer review process. As if nothing shady ever gets by peer reviewers. If you publish something in the scientific literature, you’re putting your work out there. You’re making claims, and you shouldn’t be surprised (or offended) when challenges are made to what you’ve said. Because challenging the status quo is exactly how science works, whether it’s in a subsequent publication, a blog, or on PubPeer.

Every so often you come across a paper with chemistry so awesome you get pulled in like a good novel. But even rarer still are the papers with incredibly complete “experimental” sections. I’m talking complete NMR data on every compound. Melting points. Conditions for HPLC, like retention times, injection volumes, exact column specifications, and even flow rates. But this paper in OPRD by Lipton et al may take the cake for best experimental I’ve ever seen.

Now admittedly, I don’t often read any of the process development journals. Maybe this level of attention to detail is commonplace in process development research; I can say it’s generally not in more traditional synthesis journals. In this case, the authors not only described in complete detail each and every synthesis, but they even saw it fit to include, well, a table like this for each compound:

TLC eluent information, method of visualization, and Rf values?!

This kinda work really warms the cockles of my heart. Because this is generally stuff you’d do anyway in the course of synthesis research, the authors just wrote it all down.